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1.
Methods Mol Biol ; 2805: 31-50, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39008173

RESUMEN

Cell patterning for 3D culture has increased our understanding of how cells interact among themselves and with their environment during tissue morphogenesis. Building cell communities from the bottom up with size and compositional control is invaluable for studies of morphological transitions. Here, we detail Photolithographic DNA-programmed Assembly of Cells (pDPAC). pDPAC uses a photoactive polyacrylamide gel substrate to capture single-stranded DNA on a 2D surface in large-scale, highly resolved patterns using the photomask technology. Cells are then functionalized with a complementary DNA strand, enabling cells to be temporarily adhered to distinct locations only where their complementary strand is patterned. These temporary 2D patterns can be transferred to extracellular matrix hydrogels for 3D culture of cells in biomimetic microenvironments. Use of a polyacrylamide substrate has advantages, including a simpler photolithography workflow, lower non-specific cell adhesion, and lower stiction to ECM hydrogels during release of patterned hydrogels. The protocol is equally applicable to large (cm)-scale patterns and repetitive arrays of smaller-scale cell interaction or migration experiments.


Asunto(s)
Hidrogeles , Ingeniería de Tejidos , Hidrogeles/química , Humanos , Ingeniería de Tejidos/métodos , Resinas Acrílicas/química , Adhesión Celular , Matriz Extracelular/metabolismo , Matriz Extracelular/química , Técnicas de Cultivo de Célula/métodos , Animales , Técnicas de Cultivo Tridimensional de Células/métodos
2.
Violence Vict ; 39(2): 189-203, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38955471

RESUMEN

Although intimate partner violence (IPV) is an important risk factor for child physical abuse, most IPV-exposed children are not evaluated for abusive injuries. A Community Advisory Board (CAB) was formed to (a) optimize a program to evaluate IPV-exposed children for abusive injuries and (b) inform research methods to engage IPV victims and their children. The objectives of this study were to implement and to evaluate the family violence CAB. Following best practices on CAB formation, we recruited local stakeholders with key roles as service providers, community leaders, and knowledge experts in IPV, child abuse, and emergency care. Fourteen members met bimonthly to develop a family-centered intervention and to inform research and advocacy activities. A shared memorandum of understanding outlined goals and objectives. One year after the CAB's implementation, a research assistant interviewed CAB members to understand their experiences, perceived benefits of participation, and desired improvements. Eleven CAB members, including an IPV survivor, participated. Emerging categories included (a) motivations to join the CAB (victim advocacy), (b) benefits of participation (development of relationships among members and increased acceptability of research methods), (c) facilitators of sustainability (program adaptability and development of trust), and (d) desired improvements (case-based follow-up). The CAB was successfully implemented and facilitated the development of collaborative relationships among stakeholders with key roles in IPV and child abuse. The CAB led to community member-proposed changes in research activities and clinical care for victims of IPV.


Asunto(s)
Comités Consultivos , Violencia de Pareja , Humanos , Femenino , Masculino , Niño , Violencia de Pareja/prevención & control , Maltrato a los Niños/prevención & control , Adulto , Violencia Doméstica
3.
Nat Commun ; 15(1): 5629, 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38965223

RESUMEN

Mutations that decrease or increase the activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), promotes developmental disorders and several malignancies by varying phosphatase activity. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR. Noonan Syndrome with Multiple Lentigines (NSML) patients, SHP2 knock-in mice, and ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors with high pSHP2 and pACK1 activity exhibited progressive downregulation of pY54-H3 levels and higher AR expression that correlated with disease severity. Overall, pSHP2/pY54-H3 signaling acts as a sentinel of AR homeostasis, explaining not only growth retardation, genital abnormalities and infertility among NSML patients, but also significant AR upregulation in prostate cancer patients.


Asunto(s)
Epigénesis Genética , Histonas , Homeostasis , Ratones Noqueados , Neoplasias de la Próstata , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Receptores Androgénicos , Animales , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Histonas/metabolismo , Masculino , Humanos , Ratones , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Fosforilación , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Transducción de Señal , Cromatina/metabolismo
4.
J Rheumatol ; 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38950951

RESUMEN

OBJECTIVE: Rheumatoid arthritis (RA) has been associated with an elevated dementia risk. The study aimed to examine how different diagnostic dementia definitions perform in those with RA compared to individuals without RA. METHODS: This study population included 2050 individuals (1025 with RA) from a retrospective population-based cohort in southern Minnesota and compared the performance of three code-based dementia diagnostic algorithms with medical record review diagnosis of dementia. For the overall comparison, no time frames were used, and each patient's complete medical history was used. Sensitivity analyses were performed using 1, 2, and 5-year windows around the date that dementia was identified in the medical record (reference standard). RESULTS: Algorithms performed very similarly in persons with and without RA. The algorithms generally had high specificity, negative predictive values, and accuracy, regardless of the time window studied (>88%). Sensitivity and positive predictive values varied depending on the algorithm and the time window studied. Sensitivity values ranged from 56.5% to 95.9%, and positive predictive values ranged from 55.2% to 83.1%. Performance measures declined with more restrictive time windows. CONCLUSION: Routinely collected electronic health record (EHR) data was used to define code-based dementia diagnosis algorithms with good performance (vs. diagnosis by medical record review). These results can inform future studies that use retrospective databases (especially in the same or similar EHR infrastructure) to identify dementia in individuals with RA.

5.
J Surg Orthop Adv ; 33(2): 77-79, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38995061

RESUMEN

The purpose of this study is to evaluate trends in distal clavicle excision (DCE) in association with arthroscopic rotator cuff repair (RCR) from 2010 to 2019. The National Surgical Quality Improvement Program database was queried to identify all patients who underwent arthroscopic RCR from January 1, 2010 to December 31, 2019, and was further subdivided into procedure type: (1) isolated RCR; and (2) RCR with arthroscopic or open DCE. The proportion of each surgery type, by year and within groups, was calculated. The Cochran-Armitage test for trend was used to analyze yearly proportions of RCR with concomitant DCE. In a sample size of 19,163 patients, the proportion of RCR with DCE decreased from 51.2% to 40.8% (r = -0.830; p = 0.003). Although the results of this study suggest that surgeons are performing fewer DCEs in the setting of RCR, many DCEs are still being done. (Journal of Surgical Orthopaedic Advances 33(2):077-079, 2024).


Asunto(s)
Artroscopía , Clavícula , Lesiones del Manguito de los Rotadores , Humanos , Clavícula/cirugía , Lesiones del Manguito de los Rotadores/cirugía , Masculino , Femenino , Persona de Mediana Edad , Manguito de los Rotadores/cirugía , Anciano , Estudios Retrospectivos , Bases de Datos Factuales
6.
J Surg Orthop Adv ; 33(2): 112-116, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38995069

RESUMEN

We investigated the effect of robotic assistance in a postoperative change in hip offset and the incidence of trochanteric bursitis among total hip arthroplasty (THA) patients. As part of a retrospective study of a consecutive series of patients over a 3-year period, 211 patients (102 traditional; 109 robotic) between 2013 and 2016 who underwent posterior-lateral THA were reviewed. Hip offset was measured on preoperative and postoperative anterior-posterior (AP) pelvis radiographs. The absolute change in total hip offset was higher in patients undergoing non-robotic THA than in patients undergoing robotic THA (5.98 ± 4.47 mm vs 4.33 ± 3.98 mm; p = 0.008). The rate of symptomatic trochanteric bursitis (p = 0.02) and cortisone injection was higher in non-robotic THA patients than in robotic THA patients (p = 0.002). Robotic arm-assisted THA is associated with a decreased postoperative change in hip offset, incidence of symptomatic trochanteric bursitis, and bursal steroid injections. (Journal of Surgical Orthopaedic Advances 32(4):112-116, 2023).


Asunto(s)
Artroplastia de Reemplazo de Cadera , Bursitis , Complicaciones Posoperatorias , Procedimientos Quirúrgicos Robotizados , Humanos , Artroplastia de Reemplazo de Cadera/métodos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Procedimientos Quirúrgicos Robotizados/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Articulación de la Cadera/diagnóstico por imagen
7.
Environ Model Softw ; 176: 1-14, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38994237

RESUMEN

The first phase of a national scale Soil and Water Assessment Tool (SWAT) model calibration effort at the HUC12 (Hydrologic Unit Code 12) watershed scale was demonstrated over the Mid-Atlantic Region (R02), consisting of 3036 HUC12 subbasins. An R-programming based tool was developed for streamflow calibration including parallel processing for SWAT-CUP (SWAT- Calibration and Uncertainty Programs) to streamline the computational burden of calibration. Successful calibration of streamflow for 415 gages (KGE ≥0.5, Kling-Gupta efficiency; PBIAS ≤15%, Percent Bias) out of 553 selected monitoring gages was achieved in this study, yielding calibration parameter values for 2106 HUC12 subbasins. Additionally, 67 more gages were calibrated with relaxed PBIAS criteria of 25%, yielding calibration parameter values for an additional 150 HUC12 subbasins. This first phase of calibration across R02 increases the reliability, uniformity, and replicability of SWAT-related hydrological studies. Moreover, the study presents a comprehensive approach for efficiently optimizing large-scale multi-site calibration.

8.
ACS Med Chem Lett ; 15(7): 1041-1048, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-39015276

RESUMEN

A series of novel hydroxamic acid derivatives was designed and synthesized, and their growth inhibitory activity against bloodstream form Trypanosoma brucei was evaluated. These compounds are based on conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds and bear a side pharmacophoric functionality that contains an acetohydroxamic acid moiety (CH2CONHOH) linked with the imidic nitrogen atom of the 2,6-DKP ring via an acetamido portion [CH2CON(R), R = H, CH3]. Most of these analogues were active in the midnanomolar to low micromolar range against T. brucei. (S)-Isobutyl- or (S)-benzyl-substitution on the methylene carbon located between the amine nitrogen atom and carbonyl of the 2,6-DKP ring was studied. The effect of the methyl-substitution on the nitrogen atom of the acetamido portion in the side pharmacophoric functionality was also examined. Compounds 22 and 23, bearing an isobutyl- or benzyl-substituent, respectively, and concurrently a methyl-substituent, were found to be the most potent hydroxamates of this series (IC50 = 34 and 53 nM, respectively). Both had promising selectivity over the parasite compared to mammalian cells (SI = 940 and 470, respectively). Moreover, an E/Z conformational behavior study on hydroxamic acid 18 and its methyl-substituted counterpart 21 was undertaken using NMR spectroscopy and theoretical calculations.

9.
Open Forum Infect Dis ; 11(7): ofae370, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39015348

RESUMEN

We provide updated results (11 October 2023 through 29 February 2024) from our previously conducted test-negative case-control study in Kaiser Permanente Southern California to evaluate sublineage-specific effectiveness of the BNT162b2 XBB1.5-adapted vaccine. Results suggest that XBB1.5-adapted vaccines may have reduced effectiveness against JN.1 versus XBB sublineages.

10.
Artículo en Inglés | MEDLINE | ID: mdl-39018573

RESUMEN

BACKGROUND: Despite widespread acceptance of the importance of diversity in leadership, systemic challenges in leadership attainment in orthopaedic surgery still exist for several groups. We hypothesize that women, underrepresented in medicine groups, and Asians have decreased odds of achieving program director and chairperson positions compared with peers. METHODS: Demographic data were collected from the Association of American Medical Colleges for faculty, program directors, and chairpersons in orthopaedic surgery. Odds ratios were calculated treating race, ethnicity, or sex as the predictor variables and attainment of a leadership position as the outcome, comparing the composition of program directors in 2020 and chairpersons in 2019 with faculty in 2019. RESULTS: Significantly decreased odds were found for women at 0.37 (0.264 to 0.51 [P < 0.0001]) and the Other category at 0.16 (0.065 to 0.3864 [P = 0.0001]) while significantly increased odds were found for White and Black/African American faculty at 1.32 (1.02 to 1.71 [P = 0.0314]) and 1.95 (1.17 to 3.26 [P = 0.011]), respectively, in holding program director positions. Significantly decreased odds of attaining chairpersonship were found for women at 0.17 (0.07 to 0.41 [P = 0.0075]) and Asian faculty at 0.33 (0.14 to 0.75 [P = 0.0062]) while White faculty demonstrated significantly increased odds at 2.43 (1.41 to 4.19 [P = 0.0013]). CONCLUSIONS: Women showed markedly decreased odds of leadership attainment while Black/African American faculty had increased likelihood of becoming program directors but were not markedly more likely to become chairs. Asian faculty were less likely to become program directors and markedly less likely to become chairs. While decreased odds for women were expected based on current literature, decreased odds of Asians becoming chairs and an increased likelihood of Black/African American orthopaedic surgeons becoming program directors but not attaining the role of chairs at the same rate were novel findings, revealing concerning trends for these groups.

11.
Anxiety Stress Coping ; : 1-17, 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-39021066

RESUMEN

BACKGROUND: College students with ADHD have difficulties with emotion regulation and have poorer academic skills than peers without ADHD; however, less is known regarding the relation between ADHD symptoms, maladaptive cognitive emotion regulation strategies (CERS), and learning effectiveness. OBJECTIVES: We examined whether maladaptive CERS predicted learning effectiveness, and whether this relation was moderated by ADHD symptoms. DESIGN: A cross-sectional online survey. METHODS: College students (N = 4,183; Mage = 19.24; 70.1% female) at eight universities completed a battery as part of a larger study. RESULTS: College students in our elevated ADHD group used significantly more maladaptive CERS and performed worse in three domains of learning effectiveness (i.e., Academic Self-Efficacy [ASE], Organization and Attention to Study [OAS], Stress and Time Press [STP]) than college students in our non-ADHD group. Further, ADHD symptoms moderated the relation between maladaptive CERS and OAS, such that individuals with the highest levels of ADHD symptoms were less impacted by maladaptive CERS. CONCLUSION: Increased use of maladaptive CERS is unique to ADHD rather than lack of adaptive CERS. Also, maladaptive CERS and low ADHD symptoms interact to predict poor OAS. Interventions for college students, regardless of ADHD status, should incorporate emotion regulation components to improve learning effectiveness.

12.
Am J Hypertens ; 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39022802

RESUMEN

Black race has been used to guide antihypertensive drug selection for Black patients based on predominant between race (same drug) and intra-race (different drugs) BP response patterns. Accordingly, thiazide diuretics and calcium antagonists have been recommended over renin angiotensin system (RAS) inhibitors (angiotensin receptor blockers, angiotensin converting enzyme inhibitors) and beta blockers for Black patients. Current antihypertensive drug prescribing reflects historical guidance as calcium antagonist and thiazide diuretics are prescribed more and RAS blockers less in Black than White patients. Hypertension control rates in Blacks, lag those for Whites despite their greater use of combination drug therapy and lesser use of monotherapy. This is also true across drug regimens containing any of the four recommended classes for initial therapy as well as for evidence-based combination drug therapy (calcium antagonist or thiazide diuretic + RAS blocker) regimens for which there is no known racial disparity in BP response. Current recommendations acknowledge the need for combination drug therapy in most, especially in Black patients. One exemplar comprehensive hypertension control program achieved > 80% control rates in Black and White patients with minimal racial disparity while utilizing a race-agnostic therapeutic algorithm. Black patients manifest robust, if not outsized, BP responses to diet/lifestyle modifications. Importantly, race neither appears to be a necessary nor sufficient consideration for selection of effective drug therapy. Accordingly, we urge the initiation of adequately intense race-agnostic drug therapy coupled with greater emphasis on diet/lifestyle modifications for Black patients as the cornerstone of a race-informed approach to hypertension therapeutics.

13.
medRxiv ; 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-39006427

RESUMEN

Objectives: Cerebral blood flow (CBF) measured by arterial spin labeling (ASL) is a promising biomarker for Alzheimer's Disease (AD). ASL data from multiple vendors were included in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. However, the M0 images were missing in Siemens ASL data, prohibiting CBF quantification. Here, we utilized a generative diffusion model to impute the missing M0 and validated generated CBF data with acquired data from GE. Methods: A conditional latent diffusion model was trained to generate the M0 image and validate it on an in-house dataset (N=55) based on image similarity metrics, accuracy of CBF quantification, and consistency with the physical model. This model was then applied to the ADNI dataset (Siemens: N=211) to impute the missing M0 for CBF calculation. We further compared the imputed data (Siemens) and acquired data (GE) regarding regional CBF differences by AD stages, their classification accuracy for AD prediction, and CBF trajectory slopes estimated by a mixed effect model. Results: The trained diffusion model generated the M0 image with high fidelity (Structural similarity index, SSIM=0.924±0.019; peak signal-to-noise ratio, PSNR=33.348±1.831) and caused minimal bias in CBF values (mean difference in whole brain is 1.07±2.12ml/100g/min). Both generated and acquired CBF data showed similar differentiation patterns by AD stages, similar classification performance, and decreasing slopes with AD progression in specific AD-related regions. Generated CBF data also improved accuracy in classifying AD stages compared to qualitative perfusion data. Interpretation/Conclusion: This study shows the potential of diffusion models for imputing missing modalities for large-scale studies of CBF variation with AD.

14.
CRISPR J ; 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38976494

RESUMEN

Traditional distinctions between treatment and enhancement goals for human genome editing (HGE) have animated oversight considerations, yet these categories have been complicated by the addition of prevention as a possible target for HGE applications. To assess the role these three categories might play in continued HGE governance efforts, we report on interviews with genome editing scientists and governance group members. While some accepted traditional distinctions between treatment and enhancement and rejected the latter as unacceptable, others argued that the concept of enhancement is largely irrelevant or not as morally problematic as suggested. Others described how preventive goals for HGE create gray zones where prevention and enhancement may be difficult to distinguish, which may stymie uses of HGE. We conclude by discussing the governance implications of these various understandings of treatment, prevention, and enhancement as HGE research moves beyond the treatment of serious disease to embrace longer range preventive goals.

15.
J Nurs Educ ; 63(7): 490-491, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38979736

RESUMEN

In keeping with this year's focus on how we might foster a culture of research that values and consistently adopts optimal statistical practices, this column entry highlights practices our applied researchers can take up that may help remedy the gap between recommended statistical practices and implementation. This installment specifically encourages increasing the transparency of analyses, teaming up with colleagues with quantitative expertise, and disseminating resources that highlight optimal practices. [J Nurs Educ. 2024;63(7):490-491.].


Asunto(s)
Investigación en Enfermería , Humanos , Proyectos de Investigación , Estadística como Asunto , Interpretación Estadística de Datos , Investigadores
16.
Transl Anim Sci ; 8: txae098, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39005630

RESUMEN

The National Beef Quality Audit - 2022 serves as a benchmark of the current fed steer and heifer population of the U.S. beef industry and allows comparison to previous audits as a method of monitoring industry progress. In-plant cooler assessments and collections of beef carcass data took place from July 2021 to November 2022. During in-plant evaluations, 10% of 1-d production was surveyed for quality and yield indicating characteristics of fed beef carcasses (n = 9,746 beef carcasses). Distributions of sex classes among sampled carcasses were steer (65.0%) and heifer (35.0%), whereas distributions of breed type were native (87.7%), dairy (11.3%), and Bos indicus (0.9%). Mean values were observed for USDA Yield Grades (YG; 3.3), USDA Quality Grade (QG; Choice16), marbling score (Small98), ribeye area (91.0 cm2), adjusted fat thickness (1.49 cm), hot carcass weight (401.9 kg), and KPH (2.5%). Mean overall maturity was A66, with a mean lean maturity of A56 and mean skeletal maturity of A72. There were 28.1% of carcasses identified for use in a USDA-certified beef G-Schedule Program. Defects, such as dark cutting and blood splash, were observed at 1.8% and 0.5%, respectively. Distributions of USDA YG were YG 1 (8.2%), YG 2 (30.7%), YG 3 (40.2%), YG 4 (16.6%), and YG 5 (4.3%). USDA QGs were observed at 7.5% Prime, 69.2% Choice, 16.4% Select, and 6.8% other. The results of this study provide an updated look at the current grading trends of beef carcasses in the United States to drive progress in the fed beef industry.

17.
Cureus ; 16(6): e62189, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-39006584

RESUMEN

INTRODUCTION: Low back pain (LBP) is highly prevalent and a top cause of disability-related early retirement in firefighters. Those with a lifetime history of LBP have various deficiencies that are associated with increased injury risk and absenteeism. However, the influence of working with current LBP on disability, physical performance, and other biopsychosocial factors has not been fully characterized in this population. The purpose of this study was to compare anthropometric measures, exercise habits, physical fitness/performance, disability/work ability, and other biopsychosocial factors of firefighters working with and without current LBP. METHODS: A cross-sectional study was conducted using baseline assessments from 419 full-duty career firefighters without documented work restrictions (age: 37.6 ± 8.8 y; 5 F, 414 M) who were enrolled in a regional wellness initiative in Southern California, USA. Current LBP status was determined by a questionnaire and confirmed by an interview. Anthropometric measures, patient-reported outcomes, and physical fitness tests were used to assess body mass index; body fat %; waist circumference; strengthening, cardiovascular, and flexibility exercise frequency; back and core muscular endurance; functional movement quality, perceived back-related disability, lift and carry ability, and firefighter task ability; sleep quality; and perceptions of fear and fatigue and catastrophic injustice experience. Scores for participants with and without current LBP were compared using analysis of variance and chi-square analysis. RESULTS: The point prevalence of current LBP was 19.81% (83/419). For the entire cohort, those with current LBP had significantly worse scores than those without current LBP for all assessed variables, except core muscular endurance and functional movement quality. These trends held up when analyses were stratified by age and obesity categories, and approximately half of the comparisons retained statistical significance. A significantly greater percentage of participants with current LBP were working with some level of back-related disability and/or perceived physical demand characteristics of work level below the required very heavy job demands. CONCLUSION: Nearly one-fifth of full-duty career firefighters without documented work restrictions reported having current LBP, and these individuals had deficits in several modifiable biopsychosocial factors across five health domains. These findings can help guide future research and implementation efforts in the fire service designed to improve performance, resiliency, work readiness, recovery, and quality of life, as well as to reduce impairment, disability, and absenteeism and increase presenteeism.

18.
Nat Chem ; 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-39009794

RESUMEN

Soft-matter nanoscale assemblies such as liposomes and lipid nanoparticles have the potential to deliver and release multiple cargos in an externally stimulated and site-specific manner. Such assemblies are currently structurally simplistic, comprising spherical capsules or lipid clusters. Given that form and function are intertwined, this lack of architectural complexity restricts the development of more sophisticated properties. To address this, we have devised an engineering strategy combining microfluidics and conjugation chemistry to synthesize nanosized liposomes with two discrete compartments, one within another, which we term concentrisomes. We can control the composition of each bilayer and tune both particle size and the dimensions between inner and outer membranes. We can specify the identity of encapsulated cargo within each compartment, and the biophysical features of inner and outer bilayers, allowing us to imbue each bilayer with different stimuli-responsive properties. We use these particles for multi-stage release of two payloads at defined time points, and as attolitre reactors for triggered in situ biochemical synthesis.

19.
bioRxiv ; 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-39005383

RESUMEN

Background: Neuroblastoma is a heterogeneous disease with adrenergic (ADRN)- and therapy resistant mesenchymal (MES)-like cells driven by distinct transcription factor networks. Here, we investigate the expression of immunotherapeutic targets in each neuroblastoma subtype and propose pan-neuroblastoma and cell state specific targetable cell-surface proteins. Methods: We characterized cell lines, patient-derived xenografts, and patient samples as ADRN-dominant or MES- dominant to define subtype-specific and pan-neuroblastoma gene sets. Targets were validated with ChIP- sequencing, immunoblotting, and flow cytometry in neuroblastoma cell lines and isogenic ADRN-to-MES transition cell line models. Finally, we evaluated the activity of MES-specific agents in vivo and in vitro . Results: Most immunotherapeutic targets being developed for neuroblastoma showed significantly higher expression in the ADRN subtype with limited expression in MES-like tumor cells. In contrast, CD276 (B7-H3) and L1CAM maintained expression across both ADRN and MES states. We identified several receptor tyrosine kinases (RTKs) enriched in MES-dominant samples and showed that AXL targeting with ADCT-601 was potently cytotoxic in MES-dominant cell lines and showed specific anti-tumor activity in a MES cell line-derived xenograft. Conclusions: Immunotherapeutic strategies for neuroblastoma must address the potential of epigenetic downregulation of antigen density as a mechanism for immune evasion. We identified several RTKs as candidate MES-specific immunotherapeutic target proteins for the elimination of therapy-resistant cells. We hypothesize that the phenomena of immune escape will be less likely when targeting pan-neuroblastoma cell surface proteins such as B7-H3 and L1CAM, and/or dual targeting strategies that consider both the ADRN- and MES-cell states. Key Points: Cellular plasticity influences the abundance of immunotherapeutic targets.Subtype-specific targets may be susceptible to epigenetically-mediated downregulation.Immunotherapeutic targets in development, B7-H3 and L1CAM, show "pan-subtype" expression. Importance of Study: Neuroblastoma is a lethal childhood malignancy that shows cellular plasticity in response to anti-cancer therapies. Several plasma membrane proteins are being developed as immunotherapeutic targets in this disease. Here we define which cell surface proteins are susceptible to epigenetically regulated downregulation during an adrenergic to mesenchymal cell state switch and propose immunotherapeutic strategies to anticipate and circumvent acquired immunotherapeutic resistance.

20.
J Chem Phys ; 161(3)2024 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-39007386

RESUMEN

Pressure-composition binary phase diagrams were determined for methanethiol, dimethyl sulfide, thiophene, benzothiophene, or dibenzothiophene with carbon dioxide at temperatures from 363 to 453 K and pressures from 2 to 20 MPa. Utilizing Gibbs ensemble Monte Carlo molecular simulation, phase coexistence compositions were determined, along with the impact of 4% water cosolvent on select results. Solution structure as a function of pressure and temperature is characterized via radial distribution functions. Comparison to available experimental composition data gives overall mean absolute percentage deviations of 2.2% for thiophene, 37% for methanethiol, and 99% for benzothiophene. Solubilities in a CO2-rich phase are calculated to be sufficient to allow extraction and detection of the compounds studied here via supercritical fluid chromatography and mass spectrometry as a possible analysis approach for future Mars rover missions.

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